Mitochondrial diseases represent a clinically heterogeneous group of disorders associated with the dysfunction of the mitochondrial respiratory chain (Kargul et al., 2015; Schapira, 2012). Mitochondrial dysfunction has been established as a pathophysiological hallmark of neurodegenerative diseases, such as Parkinson's, Alzheimer's, Huntington's and Lou Gehrig's Disease. Among these diseases, Parkinson's disease (PD) is the most common aging-related neurodegenerative movement disorder in the United States, with over 630,000 people living with the effects of PD and approximately 60,000 new cases identified each year (Kowal et al., 2013).
The etiology of PD is complex and may involve different genetic and environmental factors that independently or concomitantly contribute to the development of PD (Dardiotis et al., 2013; Schapira and Jenner, 2011; Trinh and Farrer, 2013).
Genetic mutations and toxic exposures have both been linked as risk factors in the development of PD>. For example, veterans were subjected to the opportunity for multiple and combined exposures to toxic chemicals, including the herbicides paraquat and Agent Orange (the mixture of two herbicides, 2,4,5-T and 2,4-D) as well as its contaminant TCDD, the organophosphate Malathion, the anti-malaria drug Chloroquine, and the solvent Trichloroethylene (TCE), all of which have been associated with an increased risk of PD (Akahoshi et al., 2009; Bortolozzi et al., 2004; Brighina et al., 2008; Cecil and Young, 2008; Fena, 2006; Hancock et al., 2008; Tanner et al., 2011; Young and Cecil, 2011; Zaheer and Slevin, 2011). An unpublished investigation based on two large population case-control studies of PD by Nelson et al. suggests a significantly increased incidence of PD in veterans who were deployed during either World War II or the Vietnam War (Laino, 2005). Today, approximately 80,000 veterans receiving care and assistance from the Department of Veterans Affairs (VA) are living with PD, and this number does not include those receiving care from other providers. Clinically, this chronic and progressive disease is characterized by resting tremor, rigidity, bradykinesia, postural instability and a broad spectrum of non-motor symptoms, such as autonomic dysfunction, cognitive deficits, depression, and sensory and sleep abnormalities (Ferrer et al., 2012; Sprenger and Poewe, 2013; Taylor et al., 2010). These symptoms ultimately lead to severe disability and reduce quality of life in these elderly patients, imposing a huge economic burden on individuals and society.
According to the Parkinson's Disease Foundation, the combined direct and indirect costs of PD in the United States that include medical expenses, social security payments and reduced employment are estimated at $25 billion per year.
Current treatments are focused mainly on alleviating motor symptoms by compensating for neurochemical deficits, but none of them have been proven to halt or slow disease progression. Therefore, development of better therapeutic agents for treating PD and other similar diseases will have immense implications in the healthcare needs of affected military personnel or civilians. No effective treatment options are available that improve the efficiency of mitochondrial function in these neurodegenerative diseases. Therefore, a need exists for compounds that are effective in inhibiting neuronal cell death and degeneration, or provide neuronal protection.